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The L-type Ca2+ channel CaV1.2 is essential for arterial myocyte excitability, gene expression and contraction. Elevations in extracellular glucose (hyperglycemia) potentiate vascular L-type Ca2+ channel via PKA, but the underlying mechanisms are unclear. Here, we find that cAMP synthesis in response to elevated glucose and the selective P2Y11 agonist NF546 is blocked by disruption of A-kinase anchoring protein 5 (AKAP5) function in arterial myocytes. Glucose and NF546-induced potentiation of L-type Ca2+ channels, vasoconstriction and decreased blood flow are prevented in AKAP5 null arterial myocytes/arteries. These responses are nucleated via the AKAP5-dependent clustering of P2Y11/ P2Y11-like receptors, AC5, PKA and CaV1.2 into nanocomplexes at the plasma membrane of human and mouse arterial myocytes. Hence, data reveal an AKAP5 signaling module that regulates L-type Ca2+ channel activity and vascular reactivity upon elevated glucose. This AKAP5-anchored nanocomplex may contribute to vascular complications during diabetic hyperglycemia., Molecular mechanisms by which glucose modulates L-type Ca2+ channel activity and vascular reactivity are unclear. Here the authors report a nanocomplex orchestrated by AKAP5 that facilitates local purinergic stimulation of L-type Ca2+ channels and vasoconstriction during diabetic hyperglycemia.

Background There is no current consensus on the management of large hiatal hernias concomitant with performance of a sleeve gastrectomy procedure. Proposed solutions have included performing a modified Nissen fundoplication, performing cruroplasty alone, utilizing the Linx device, performing cruroplasty with reinforcement material, and avoiding the sleeve procedure altogether in favor of a bypass procedure in order to minimize gastroesophageal reflux. Urinary bladder matrix (UBM) represents a biologically derived material for use in hiatal hernia repair reinforcement with the potential to improve durability of repair without incurring the risks of other reinforcement materials. Methods This study reports the results of a retrospective chart review of 32 cases of large hiatal hernia repair utilizing both primary crural repair and UBM reinforcement concomitant with laparoscopic sleeve gastrectomy by a single surgeon. Hernia diameter averaged 6 cm (range 4-9 cm). After an average of 1 year followup, 30 patients were assessed for subjective symptoms of gastroesophageal reflux (GERD) using the Gastroesophageal Reflux Disease-Health Related Quality of Life (GERD-HRQL) score. Twenty patients were evaluated with either upper gastrointestinal (GI) series, endoscopy, or both. Results Each repair was successful and completed laparoscopically concomitant with sleeve gastrectomy. Anterior and posterior cruroplasty was performed using interrupted 0-Ethibond suture using the Endostitch device. The UBM graft exhibited favorable handling characteristics placed as a keyhole geometry sutured to the crura with absorbable suture. A careful chart review was undertaken to assess for complications. There have been no reoperations. After a median of 12 months (range, 4-27 months) of followup, an assessment of recurrences or long-term complications was completed. Median GERD-HRQL score was 6, with a range of 0 to 64 (of possible 75), indicating very low-level reflux symptomatology. Follow-up upper GI radiographs or endoscopy were obtained in 20 cases and show intact repairs. Conclusion In this series of 32 cases, laparoscopic cruroplasty with UBM graft reinforcement has been effective and durable at 12 months of followup. This technique may offer one satisfactory solution for large hiatal hernia repair concomitant with laparoscopic sleeve gastrectomy that may achieve a durable repair with low GERD symptoms.

Regulation of colonic motility depends on the integrity of enteric inhibitory neurotransmission mediated by nitric oxide (NO), purine neurotransmitters, and neuropeptides. Intramuscular interstitial cells of Cajal (ICC-IM) and platelet-derived growth factor receptor-α-positive (PDGFRα+) cells are involved in generating responses to NO and purine neurotransmitters, respectively. Previous studies have suggested a decreased nitrergic and increased purinergic neurotransmission in KitW/KitW-v ( W/Wv) mice that display lesions in ICC-IM along the gastrointestinal tract. However, contributions of NO to these phenotypes have not been evaluated. We used small-chamber superfusion assays and HPLC to measure the spontaneous and electrical field stimulation (EFS)-evoked release of nicotinamide adenine dinucleotide (NAD+)/ADP-ribose, uridine adenosine tetraphosphate (Up4A), adenosine 5′-triphosphate (ATP), and metabolites from the tunica muscularis of human, monkey, and murine colons and circular muscle of monkey colon, and we tested drugs that modulate NO levels or blocked NO receptors. NO inhibited EFS-evoked release of purines in the colon via presynaptic neuromodulation. Colons from W/Wv, Nos1−/−, and Prkg1−/− mice displayed augmented neural release of purines that was likely due to altered nitrergic neuromodulation. Colons from W/Wv mice demonstrated decreased nitrergic and increased purinergic relaxations in response to nerve stimulation. W/Wv mouse colons demonstrated reduced Nos1 expression and reduced NO release. Our results suggest that enhanced purinergic neurotransmission may compensate for the loss of nitrergic neurotransmission in muscles with partial loss of ICC. The interactions between nitrergic and purinergic neurotransmission in the colon provide novel insight into the role of neurotransmitters and effector cells in the neural regulation of gastrointestinal motility. NEW & NOTEWORTHY This is the first study investigating the role of nitric oxide (NO) and intramuscular interstitial cells of Cajal (ICC-IM) in modulating neural release of purines in colon. We found that NO inhibited release of purines in human, monkey, and murine colons and that colons from KitW/KitW-v ( W/Wv) mice, which present with partial loss of ICC-IM, demonstrated augmented neural release of purines. Interactions between nitrergic and purinergic neurotransmission may affect motility in disease conditions with ICC-IM deficiencies.

Introduction. Laparoscopic sleeve gastrectomy is a widely utilized and effective surgical procedure for dramatic weight loss in obese patients. Leak at the sleeve staple line is the most serious complication of this procedure, occurring in 1–3% of cases. Techniques to minimize the risk of sleeve gastrectomy leaks have been published although no universally agreed upon set of techniques exists. This report describes a single-surgeon experience with an approach to sleeve leak prevention resulting in a progressive decrease in leak rate over 5 years. Methods. 1070 consecutive sleeve gastrectomy cases between 2012 and 2016 were reviewed retrospectively. Patient characteristics, sleeve leaks, and percent body weight loss at 6 months were reported for each year. Conceptual and technical changes aimed towards leak reduction are presented. Results. With the implementation of the described techniques of the sleeve gastrectomy, the rate of sleeve leaks fell from 4% in 2012 to 0% in 2015 and 2016 without a significant change in weight loss, as depicted by 6-month change in body weight and percent excess BMI lost. Conclusion. In this single-surgeon experience, sleeve gastrectomy leak rate has fallen to 0% since the implementation of specific technical modifications in the procedure.

Platelet-derived growth factor receptor alpha (PDGFRα)+ cells are distributed into distinct morphological groups within the serosal, muscular, and submucosal layers as well as the myenteric and deep muscular plexi. PDGFRα+ cells directly interact with interstitial cells of Cajal (ICC) and smooth muscle cells (SMC) in gastrointestinal smooth muscle tissue. These three cell types, SMC, ICC, and PDGFRα+ cells (SIP cells), form an electrical syncytium, which dynamically regulates gastrointestinal motility. We have previously reported the transcriptomes of SMC and ICC. To complete the SIP cell transcriptome project, we obtained transcriptome data from jejunal and colonic PDGFRα+ cells. The PDGFRα+ cell transcriptome data were added to the Smooth Muscle Genome Browser that we previously built for the genome-scale gene expression data of ICC and SMC. This browser provides a comprehensive reference for all transcripts expressed in SIP cells. By analyzing the transcriptomes, we have identified a unique set of PDGFRα+ cell signature genes, growth factors, transcription factors, epigenetic enzymes/regulators, receptors, protein kinases/phosphatases, and ion channels/transporters. We demonstrated that the low voltage-dependent T-type Ca2+ channel Cacna1g gene was particularly expressed in PDGFRα+ cells in the intestinal serosal layer in mice. Expression of this gene was significantly induced in the hyperplasic PDGFRα+ cells of obstructed small intestine in mice. This gene was also over-expressed in colorectal cancer, Crohn's disease, and diverticulitis in human patients. Taken together, our data suggest that Cacna1g exclusively expressed in serosal PDGFRα+ cells is a new pathological marker for gastrointestinal diseases.

Background and objectives Hiatal hernias are repaired laparoscopically with increasing use of reinforcement material. Both synthetic and biologically derived materials reduce the recurrence rate compared to primary crural repair. Synthetic mesh introduces complications, such as mesh erosion, fibrosis, and infection. Urinary bladder matrix (UBM) represents a biologically derived material for use in hiatal hernia repair reinforcement with the potential to improve durability of repair without incurring the risks of other reinforcement materials. Methods The 15 cases presented involved hiatal hernia repair with primary crural repair with UBM reinforcement and fundoplication. Patients were followed for an average of 3 years, and were assessed with upper gastrointestinal (GI) series, endoscopy, and assessments of subjective symptoms of gastroesophageal reflux disease (GERD). Results Hernia diameters averaged 6 cm. Each repair was successful and completed laparoscopically. UBM exhibited favorable handling characteristics when placed as a horseshoe-type graft sutured to the crura. One patient underwent endoscopic balloon dilatation of a mild postoperative stenosis that resolved. No other complications occurred. In more than 3 years of follow-up, there have been no recurrences or long-term complications. GERD-health-related quality of life (HRQL) scores averaged 6 (range, 0-12, of a possible 50), indicating little reflux symptomatology. Follow-up upper GI series were obtained in 9 cases and showed intact repairs. An upper endoscopy was performed in 8 patients and showed no recurrences. Conclusion Surgeons may safely use laparoscopic fundoplication with UBM reinforcement for successful repair of hiatal hernias. In this series, repairs with UBM grafts have been durable at 3 years of follow-up and may serve as an alternative to synthetic mesh reinforcement of hiatal hernia repairs.

Objectives: The purpose of this study was to evaluate the utility of positron emission tomography with F18-fluorodeoxyglucose in the preoperative evaluation and staging of malignant mesothelioma in patients who were candidates for aggressive combined modality therapy. Methods: Eighteen consecutive patients with biopsy-proven malignant mesothelioma underwent positron emission tomographic scanning. The results of positron emission tomographic imaging were compared with results obtained by computed tomography, mediastinoscopy, thoracoscopy, and pathologic examination of surgical specimens. All patients fasted and received an average of 14.5 ± 2.7 mCi of F18-fluorodeoxyglucose for positron emission tomographic scanning. Attenuation-corrected whole-body and regional emission images of the chest and upper abdomen were acquired and formatted into transaxial, coronal, and sagittal images. Results: All primary malignant mesotheliomas accumulated F18-fluorodeoxyglucose, and the mean standardized uptake value was 7.6 (range, 3.33-14.85; n=9). There were no false-negative results of positron emission tomography. Identification of occult extrathoracic metastases by positron emission tomography was the basis for excluding two patients from surgical therapy. There were two false-positive results of positron emission tomography: increased F18-fluorodeoxyglucose uptake in the contralateral chest that was negative by thoracoscopic biopsy (n = 1) and increased abdominal F18-fluorodeoxyglucose uptake after partial colectomy for diverticular disease (n = 1). Conclusions: Positron emission tomography can identify malignant pleural mesothelioma and appears to be a useful noninvasive staging modality for patients being considered for aggressive combined modality therapy. (J Thorac Cardiovasc Surg 2000;120:128-33)